Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) represents a worldwide health challenge, ranking globally as the third most common cause of cancer-related mortality. Current advancements in the HCC therapeutic armamentarium succeeded in challenging HCC conventional therapy. Systemic therapies including tyrosine kinase inhibitors and immune checkpoint inhibitors (ICIs) come at the forefront of novel HCC therapeutic modalities. However, emerging drug resistance remains an obstacle during HCC therapy. According to the ongoing genomic analysis of HCC, a complex mutational landscape lies behind HCC pathogenesis and hence, affects the response of the tumor to the applied therapy. This review aims at categorizing and summarizing the different resistance mechanisms confronting tyrosine kinase inhibitors, represented by sorafenib, as well as ICIs, during HCC therapy. In addition, giving an insight into how genomic heterogeneity can influence the response of HCC to the aforementioned therapies. ABSTRACT: Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms.